Management of Septic Shock

Severe sepsis is a common disease process affecting some 2-11% of hospital admissions in the US. Severe sepsis and septic shock are associated with considerable morbidity and mortality, and account for a large part of intensive care unit costs. Until recently, the management of septic shock relied on the treatment of underlying infection with antimicrobial agents and surgical removal of any infectious source, and individual support of failing organs. However, in the last few years we have seen huge strides being made in our understanding of the pathophysiology of the sepsis response, and in our ability to manipulate that response. In the last couple of years these advances have come to fruition with the development of a drug, drotrecogin alfa, which specifically reduces mortality from this all too often fatal disease. While intensive early resuscitation remains the cornerstone of management, new approaches are beginning to form part of sepsis management protocols and will lead to improved outcomes for patients with this disease process.     

Optimum treatment of severe sepsis and septic shock: evidence in support of the recommendations

Severe sepsis and septic shock are among the most common causes of death in noncoronary intensive care units. The incidence of sepsis has been increasing over the past two decades, and is predicted to continue to rise over the next 20 years. While our understanding of the complex pathophysiologic alterations that occur in severe sepsis and septic shock has increased greatly asa result of recent clinical and preclinical studies, mortality associated with the disorder remains unacceptably high. Despite these new insights, the cornerstone of therapy continues to be early recognition, prompt initiation of effective antibiotic therapy, and source control, and goal-directed hemodynamic, ventilatory,and metabolic support as necessary. To date, attempts to reduce mortality with innovative, predominantly anti-inflammatory therapeutic strategies have been extremely disappointing. Observations of improved outcomes with physiologic doses of corticosteroid replacement therapy and activated protein C (drotrecogin alfa[activated]) have provided new adjuvant therapies for severe sepsis and septic shock in selected patients. This article reviews the components of sepsis management and discusses the available evidence in support of these recommendations. In addition, there is a discussion of some promising new strategies.     

成人严重感染与感染性休克血流动力学监测及支持指南(草案)

严重感染(severe sepsis)及其相关的感染性休克(septic shock)和多器官功能障碍综合征(multiple organ dysfunction syndrome,MODS)是当前重症加强治疗病房(ICU)的主要死亡原因,也是当代重症医学面临的主要焦点及难点。在美国,每年有75万的严重感染病例发生,超过了充血性心力衰竭或乳腺癌、结肠癌和艾滋病的患病数总和,病死率在20%～63%左右,与急性心肌梗死的院外病死率相近,而且患病率以每年1.5%的比例增长,预计到2010年和2020年,严重感染的患病人数将达到93万和110万。美国每年的相关治疗     

Novel potential therapies for septic shock

Sepsis is the systemic inflammatory response syndrome secondary to a local infection. Septic shock, the severe complication of sepsis associated with refractory hypotension, is frequently a near-fatal condition requiring prompt diagnosis and management. Although the recent years have been associated with considerable improvements in the knowledge of the pathophysiology of the disease and remarkable advances have been achieved in sepsis treatment, the morbidity and mortality of this disease are still unacceptably high. In this review, we will briefly discuss the ongoing standard treatment of septic shock and describe novel potential therapies, aiming to improve hemodynamic support and/or control inflammatory response in sepsis. These therapies were associated with benefits in experimental studies and have been tested or are currently under testing in randomized controlled studies with septic patients.     

Management of sepsis during the early "golden hours"

Severe sepsis and septic shock are common causes of morbidity and mortality. Interventions directed at specific endpoints, when initiated early in the "golden hours" of patient arrival at the hospital, seem to be promising. Early hemodynamic optimization, administration of appropriate antimicrobial therapy, and effective source control of infection are the cornerstones of successful management. In patients with vasopressor-dependent septic shock, provision of physiologic doses of replacement steroids may result in improved survival. Administration of drotrecogin alfa (activated), (activated protein C) has been shown to improve survival in patients with severe sepsis and septic shock who have a high risk of mortality. In this article we review the multi-modality approach to early diagnosis and intervention in the therapy of patients with severe sepsis and septic shock.     

Management of a patient with severe sepsis

Severe sepsis and septic shock affect more than 700,000 people annually and represent approximately $17 billion annually in health care costs. Mortality in patients with 3 or more failed organs is up to 70%. Early identification and prevention of severe sepsis and septic shock are key factors in impacting mortality rates. Health care providers must be knowledgeable in early identification and aggressive management. This case presentation outlines the components of care identified in the literature in the early and ongoing management of patients with severe sepsis and septic shock.     

Pharmacologic treatment related to severe sepsis

Severe sepsis is a complex syndrome often resulting in multiple organ dysfunction. This is an extremely challenging problem to manage in the intensive care unit, with mortality rates remaining at unacceptably high levels. Death of patients afflicted by this condition generally results from organ dysfunction syndromes related to hypoperfusion abnormalities. Management of patients with severe sepsis or septic shock can be very complex and challenging, utilizing a significant amount of resources. Pharmacologic support of patients with severe sepsis or septic shock primarily involves agents to support and improve perfusion at the microvascular level. It is important to understand the pharmacologic properties of the medications utilized to manage patients with these conditions. The information presented in this article is based on the best evidence currently available in order to assist the critical care nurse in understanding the pharmacologic therapy related to treatment of severe sepsis and septic shock.     

Surviving sepsis campaign in Brazil

Severe sepsis and septic shock have long been a challenge in intensive care because of their common occurrence, high associated costs of care, and significant mortality. The Surviving Sepsis Campaign (SSC) was developed in an attempt to address clinical inertia in the adoption of evidence-based strategies. The campaign relies on worldwide support from professional societies and has gained consensus on the management of patients with severe sepsis. The guidelines have subsequently been deployed into two bundles, with each bundle component sharing a common relationship in time. The widespread adoption of such evidence-based practice in clinical care has been disappointingly slow despite the quantifiable benefits regarding mortality. In Brazil, a country of continental dimensions with a heterogeneous population and unequal access to health services, this reality is no different. From 2004 to 2007, four prospective studies were published describing the country's reality. In the multicenter Promoting Global Research Excellence in Severe Sepsis (PROGRESS) Study, the in-hospital mortality rate was higher in Brazil when compared with other countries: 56% against 30% in developed countries and 45% in other developing countries. During these 2.5 years of the campaign in Brazil, 43 hospitals have been receiving the necessary training to put in practice the recommended measures in all Brazilian regions, except for the North. The idea of the campaign is based on a 25% reduction in the relative risk of death from severe sepsis and septic shock within 5 years in the SSC-participating Brazilian hospitals. Ideally, the mortality rate should come to a 41.2% level subject to the 2009 deadline. This article aims to describe the actual scenario of the SSC implementation in Brazilian institutions and to report on some initiatives that have been used to overcome barriers.     

Sepsis incidence and outcome: contrasting the intensive care unit with the hospital ward

OBJECTIVE: To describe the outcome of patients with sepsis according to location on a ward or in an intensive care unit. DESIGN: Prospective multicentered observational study. SETTING: Three academic hospitals in Madrid, Spain. PATIENTS: Consecutive patients with sepsis admitted to participating hospitals from March 1 to June 30, 2003. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During the study period, 15,852 patients >18 yrs of age were admitted. Sepsis was identified in 702 patients, giving an estimated cumulative incidence rate of 367 cases per 100,000 adult area residents per year and a cumulative incidence rate among patients admitted to the hospital of 4.4%. Most septic patients had a community-acquired infection (71%). Severe sepsis developed in 199 patients (incidence rate, 104 cases per 100,000 adult area residents per year), and 59 patients developed septic shock (incidence rate, 31 cases per 100,000 adult area residents per year). Most of the patients met the criteria for severe sepsis or septic shock on the same day that they would have qualified for the septic status one step down the scale. In the other patients, the median time between sepsis and severe sepsis was 2 days (interquartile range, 2-5) and between severe sepsis and septic shock was 3 days (interquartile range, 1-4). Only 32% of severe sepsis patients received intensive care. The hospital mortality for all septic patients was 12.8%; for severe sepsis, 20.7%; and for septic shock, 45.7%. CONCLUSIONS: This study shows the high incidence of sepsis in a general population of patients admitted to hospital. A significant proportion of patients with severe sepsis are not transferred to the intensive care unit.     

Epidemiology of severe sepsis in Japanese intensive care units: A prospective multicenter study

Severe sepsis is a leading cause of morbidity and mortality in the intensive care unit (ICU). We conducted a prospective multicenter study to evaluate epidemiology and outcome of severe sepsis in Japanese ICUs. The patients were registered at 15 general critical care centers in Japanese tertiary care hospitals when diagnosed as having severe sepsis. Of 14,417 patients, 624 (4.3%) were diagnosed with severe sepsis. Demographic and clinical characteristics at enrollment (Day 1), physiologic and blood variables on Days 1 and 4, and mortality were evaluated. Mean age was 69.0 years, and initial mean Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores were 23.4 and 8.6, respectively. The 28-day mortality was 23.1%, and overall hospital mortality was 29.5%. SOFA score and disseminated intravascular coagulation (DIC) score were consistently higher in nonsurvivors than survivors on Days 1 and 4. SOFA score, DIC score on Days 1 and 4, and hospital mortality were higher in patients with than without septic shock. SOFA score on Days 1 and 4 and hospital mortality were higher in patients with than without DIC. Logistic regression analyses showed age, presence of septic shock, DIC, and cardiovascular dysfunction at enrollment to be predictors of 28-day mortality and presence of comorbidity to be an additional predictor of hospital mortality. Presence of septic shock or DIC resulted in approximately twice the mortality of patients without each factor, whereas the presence of comorbidity may be a significant predictor of delayed mortality in severe sepsis.     

Incidence and mortality of severe sepsis in surgical intensive care patients: the influence of patient gender on disease process and outcome

Objective: Laboratory studies demonstrated significant detrimental effects of male sex-steroids (testosterone) on immune functions following hemorrhagic shock and soft-tissue trauma. Moreover, better survival of female mice subjected to severe sepsis was observed when compared to male animals. The aims of the present study were to evaluate whether or not gender differences regarding incidence and mortality of severe sepsis do exist in surgical intensive care patients and to elucidate the influence of patient age on incidence and mortality of severe sepsis/septic shock.¶Design: Data base review of prospectively collected data from surgical intensive care patients.¶Setting: Surgical intensive care unit of the department of surgery of a university hospital.¶Patients: Prospectively collected data of 4218 intensive care patients (2709 male, 1509 female).¶Results: Significantly fewer female patients were referred to the intensive care unit (6.6 % vs 10.8 % of all patients; P < 0.05) leading to a significantly smaller proportion of female intensive care patients (35.8 % vs 64.2 %). No gender differences regarding number of failing organs or surgical procedure (exception vascular surgery) were observed in patients with and without severe sepsis/septic shock, indicating that the patients studied are comparable regarding general health prior to admission to SICU. Among all female patients referred to SICU only 7.6 % developed severe sepsis/septic shock, while 10.4 % of all male patients suffered from severe sepsis or septic shock (P < 0.05). This gender difference results from a significantly lower incidence of severe sepsis/septic shock in female patients between 60 and 79 years. No gender difference regarding mortality rates of severe sepsis/septic shock was observed (men 64.9 %, women 65.5 %).¶Conclusions: Our results indicate a significantly smaller number of female patients requiring intensive care as well as a significantly lower incidence of severe sepsis/septic shock in female intensive care patients. Mortality from severe sepsis/septic shock, however, is not affected by gender.     

The epidemiology of the systemic inflammatory response

Objective: To examine the incidence, risk factors, aetiologies and outcome of the various forms of the septic syndromes (the systemic inflammatory response syndrome [SIRS] sepsis, severe sepsis, and septic shock) and their relationships with infection.¶Design: Review of published cohort studies examining the epidemiology of the septic syndromes, with emphasis on intensive care unit (ICU) patients.¶Results: The prevalence of SIRS is very high, affecting one-third of all in-hospital patients, and > 50 % of all ICU patients; in surgical ICU patients, SIRS occurs in > 80 % patients. Trauma patients are at particularly high risk of SIRS, and most these patients do not have infection documented. The prevalence of infection and bacteraemia increases with the number of SIRS criteria met, and with increasing severity of the septic syndromes. About one-third of patients with SIRS have or evolve to sepsis. Sepsis may occur in approximately 25 % of ICU patients, and bacteraemic sepsis in 10 %. In such patients, sepsis evolves to severe sepsis in > 50 % of cases, whereas evolution to severe sepsis in non-ICU patients is about 25 %. Severe sepsis and septic shock occur in 2 %–3 % of ward patients and 10 %–15 % or more ICU patients, depending on the case-mix; 25 % of patients with severe sepsis have shock. There is a graded severity from SIRS to sepsis, severe sepsis and septic shock, with an associated 28-d mortality of approximately 10 %, 20 %, 20 %–40 %, and 40 %–60 %, respectively. Mortality rates are similar within each stage, whether infection is documented or not, and microbiological characteristics of infection do not substantially influence outcome, although the source of infection does. While about three of four deaths occur during the first months after sepsis, the septic syndromes significantly impact on long-term outcome, with an estimated 50 % reduction of life expectancy over the following five years. The major determinants of outcome, both short-term and long-term, of patients with sepsis are the severity of underlying diseases and comorbidities, the presence of shock and organ failures at onset of sepsis or evolving thereafter. It has been estimated that two-thirds of the overall mortality can be attributed to sepsis.¶Conclusions: The prevalence of sepsis in ICU patients is very high, and most patients have clinically or microbiologically documented infection, except in specific subset of patients. The prognosis of septic syndromes is related to underlying diseases and the severity of the inflammatory response and its sequelae, reflected in shock and organ dysfunction/failures.     

Activated partial thromboplastin time waveform analysis: a new tool to detect infection?

OBJECTIVE: An abnormality of the optical transmission waveform obtained during measurement of the activated partial thromboplastin time (aPTT) has been described to identify a high-risk intensive care unit population consisting of patients with sepsis or with higher mortality rates than patients with normal aPTT waveforms. We investigated the abnormal aPTT biphasic waveform as a diagnostic and prognostic marker of infection. DESIGN: Prospective, observational study investigating the predictive value of aPTT waveform analysis for the diagnosis and prognosis of sepsis. SETTING: Surgical intensive care unit of a university hospital. PATIENTS: We studied 187 consecutive patients who fulfilled at least two or more criteria of the systemic inflammatory response syndrome at admission or during intensive care stay and classified as having systemic inflammatory response syndrome, sepsis, severe sepsis, or septic shock during an 8-month period. INTERVENTIONS: Laboratory analyses including aPTT waveform analysis and procalcitonin and C-reactive protein concentrations were measured at days 1-3. MEASUREMENTS AND MAIN RESULTS: The final diagnoses were systemic inflammatory response syndrome in 49%, sepsis in 16%, severe sepsis in 12%, and septic shock in 23% of patients. On day 1, the biphasic waveform was significantly more abnormal in patients with severe sepsis or septic shock than in patients with systemic inflammatory response syndrome or sepsis. The biphasic waveform was more accurate than procalcitonin and C-reactive protein for differentiating patients with severe sepsis and septic shock, with 90% sensitivity and 92% negative predictive value. Biphasic waveform values were significantly more abnormal during days 1-3 in septic nonsurvivors than in survivors and nonseptic nonsurvivors. The biphasic waveform exhibited the best specificity (91%) and negative predictive value (98%) for the prognosis of sepsis-related mortality on day 3. CONCLUSIONS: In intensive care units, when the analyzer is available, aPTT waveform analysis is an inexpensive, rapid, effective, and readily available tool providing information for the diagnosis of severe sepsis and the prognosis of septic patients.     

Treatment of impaired perfusion in septic shock

Severe sepsis and septic shock are relatively common problems in intensive care. The mortality in septic shock is still high, and the main causes of death are multiple organ failure and refractory hypotension. Impaired tissue perfusion due to hypovolemia, disturbed vasoregulation and myocardial dysfunction contribute to the multiple organ dysfunction. Treatment of hemodynamics in septic shock consists of appropriate fluid therapy guided by invasive monitoring combined with vasoactive drugs aiming to correct hypotension and inappropriately low cardiac output. The drug of choice for low vascular resistance is norepinephrine, while insufficient myocardial contractility is commonly treated with dobutamine. The use of norepinephrine seems to be associated with better prognosis as compared to results from the use of dopamine or epinephrine. In septic shock, vasopressin levels are low, and therefore, vasopressin has been advocated as a vasopressor. Its effectiveness and safety have not yet been documented, and so far it is regarded as an experimental treatment Recent data support the use of corticosteroid, at least in some of the patients with septic shock. Also, activated protein C, a drug with anti-inflammatory and antithrombotic properties, decreases mortality in patients with septic shock.     

Treatment of impaired perfusion in septic shock

Severe sepsis and septic shock are relatively common problems in intensive care. The mortality in septic shock is still high, and the main causes of death are multiple organ failure and refractory hypotension. Impaired tissue perfusion due to hypovolemia, disturbed vasoregulation and myocardial dysfunction contribute to the multiple organ dysfunction. Treatment of hemodynamics in septic shock consists of appropriate fluid therapy guided by invasive monitoring combined with vasoactive drugs aiming to correct hypotension and inappropriately low cardiac output. The drug of choice for low vascular resistance is norepinephrine, while insufficient myocardial contractility is commonly treated with dobutamine. The use of norepinephrine seems to be associated with better prognosis as compared to results from the use of dopamine or epinephrine. In septic shock, vasopressin levels are low, and therefore, vasopressin has been advocated as a vasopressor. Its effectiveness and safety have not yet been documented, and so far it is regarded as an experimental treatment. Recent data support the use of corticosteroid, at least in some of the patients with septic shock. Also, activated protein C, a drug with anti-inflammatory and antithrombotic properties, decreases mortality in patients with septic shock.     

外科重症监护室645例脓毒症患者临床流行病学调查

目的了解脓毒症在外科重症监护室（SICU）的发生情况。方法收集2003年1月～2004年12月上海市中西医结合医院SICU入住病例645例，统计全身炎症反应综合征（SIRS）、脓毒症、严重脓毒症和脓毒性休克的发生率、病死率及其与年龄、性别的关系，以及在住院时间上的差异。结果术后第1日SIRS的发生率为63．7％。术后第2日为49．8‰，在SICU期间SIRS发生率为74．3％；未发生SIRS组无死亡病例，发生SIRS组病死率为6．26％。脓毒症发生率为27．0％，严重脓毒症为10．9％，脓毒性休克为7．0％；其病死率分别为14．94％、34．29％和51．11％。脓毒症和非脓毒症患者在年龄上存在差异（P〈0．01），老年人更易发生；在性别上存在差异（P〈0．01）．男性比女性更易发生。在住院时间上脓毒症和非脓毒症患者间差异有显著性（P〈0．01）。结论脓毒症在SICU较为常见，有高龄、男性易发生的特点，严重影响患者预后；须重视明确定义，提高治疗效应。     

Elevated nucleosome levels in systemic inflammation and sepsis

OBJECTIVE: Multiple organ dysfunction syndrome is a frequent complication of severe sepsis and septic shock and has a high mortality. We hypothesized that extensive apoptosis of cells might constitute the cellular basis for this complication. DESIGN: Retrospective study. SETTING: Medical and surgical wards or intensive care units of two university hospitals. PATIENTS: Fourteen patients with fever, 15 with systemic inflammatory response syndrome, 32 with severe sepsis, and eight with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We assessed circulating levels of nucleosomes, specific markers released by cells during the later stages of apoptosis, with a previously described enzyme-linked immunosorbent assay in these 69 patients with fever, systemic inflammatory response syndrome, severe sepsis, or septic shock. Severity of multiple organ dysfunction syndrome was assessed with sepsis scores, and clinical and laboratory variables. Elevated nucleosome levels were found in 64%, 60%, 94%, and 100% of patients with fever, systemic inflammatory response syndrome, severe sepsis, or septic shock, respectively. These levels were significantly higher in patients with septic shock as compared with patients with severe sepsis, systemic inflammatory response syndrome, or fever, and in nonsurvivors as compared with survivors. In patients with advanced multiple organ dysfunction syndrome, nucleosome levels correlated with cytokine plasma levels as well as with variables predictive for outcome. CONCLUSIONS: Patients with severe sepsis and septic shock have elevated plasma levels of nucleosomes. We suggest that apoptosis, probably resulting from exposure of cells to excessive amounts of inflammatory mediators, might by involved in the pathogenesis of multiple organ dysfunction syndrome.     

Current role of high dose vitamin C in sepsis management: A concise review

Sepsis and septic shock are common diagnoses for patients requiring intensive care unit admission and associated with high morbidity and mortality. In addition to aggressive fluid resuscitation and antibiotic therapy, several other drugs have been tried as adjuvant therapies to reduce the inflammatory response and improve outcomes. Vitamin C has been shown to have several biological actions, including anti-inflammatory and immunomodulatory effects, which may prove beneficial in sepsis management. Initial trials showed improved patient outcomes when high dose vitamin C was used in combination with thiamine and hydrocortisone. These results, along with relative safety of high-dose (supra-physiological) vitamin C, encouraged physicians across the globe to add vitamin C as an adjuvant therapy in the management of sepsis. However, subsequent large-scale randomised control trials could not replicate these results, leaving the world divided regarding the role of vitamin C in sepsis management. Here, we discuss the rationale, safety profile, and the current clinical evidence for the use of high-dose vitamin C in the management of sepsis and septic shock.